A phase I study to evaluate the safety,tolerability, pharmacodynamic and pharmacokinetic profiles of ocular GLH8NDE in healthy male adults

GLH8NDE, a derivative of eupatilin, is currently under development to treat dry eye disease. We conducted a randomized, double‐masked, placebo‐controlled, single‐ and multiple‐day study to evaluate safety, tolerability, pharmacodynamics, and pharmacokinetics of ocular GLH8NDE in healthy male adults. Subjects randomly received topical ocular dosing of GLH8NDE or its matching placebo for a day, then for 7 consecutive days with a 62‐h washout at one of the following daily doses: 9, 18, 36 (Koreans), and 36 mg (Whites). The study drug was administered in divided doses over 10 h with 2‐ or 5‐h intervals. Thirty‐nine (97.5%) out of 40 subjects completed the study. A total of 17 subjects experienced 31 treatment‐emergent adverse events, all of which were mild in severity and recovered without sequelae. Neither pathological changes in eye compartments nor clinically significant systemic effects were observed. GLH8NDE was rapidly absorbed reaching the peak concentration within 0.25–0.75 h postdose. The systemic exposure as measured by area under the concentration‐time curve from time of administration up to the time of the last quantifiable concentration (AUC_last) after single‐day administration of the same dose was 109% higher in Koreans than in Whites. In conclusion, GLH8NDE was safe and well‐tolerated in healthy Korean and White male adults at 9–36 mg/day after single‐ and multiple‐day administrations.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

GLH8NDE (7‐carboxymethyloxy‐3′,4′,5′‐trimethoxy flavone) is a derivative of eupatilin, which is currently under clinical development to treat dry eye disease (DED). GLH8NDE has been effective in various experimentally induced DED animal models. Ocular GLH8NDE has never been studied in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This phase I study evaluated the safety, tolerability, pharmacodynamic, and pharmacokinetic profiles of ocular GLH8NDE in humans. In addition, the ethnic difference in the systemic exposure to GLH8NDE was assessed between Korean and White healthy male adults.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Ocular doses of GLH8NDE from 9 to 36 mg per day after single‐ and multiple‐day administrations were safe and well‐tolerated in Korean and White healthy male adults. GLH8NDE was rapidly absorbed in a dose‐proportional manner. The systemic exposure to GLH8NDE was higher in Koreans than in Whites. GLH8NDE at 9 and 36 mg per day increased tear break‐up time (TBUT) from baseline whereas TBUT was decreased in the placebo group.

• HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?

This study shows that GLH8NDE is safe and well‐tolerated in healthy Korean and White male adults over the dose range of 9–36 mg per day. GLH8NDE has a potential to be developed as a useful treatment option for DED. Further research should take account the ethnic differences in the systemic exposure to GLH8NDE.     

Pharmacokinetics and safety of cenobamate,a novel antiseizure medication,in healthy Japanese,and an ethnic comparison with healthy non‐Japanese

Cenobamate (XCOPRI and ONTOZRY) is a novel antiseizure medication for the treatment of focal‐onset seizures. Nonetheless, there is limited information on the pharmacokinetics (PKs), safety, and efficacy of cenobamate in Asian people, including Japanese people. This study aimed to evaluate the PKs and safety of cenobamate after a single oral dose in healthy Japanese subjects and to compare the PKs with that reported in non‐Japanese subjects. A randomized, double‐blind, placebo‐controlled, single ascending dose study was conducted at four dose levels of 50, 100, 200, and 400 mg. Subjects were randomly assigned to cenobamate or placebo in a 6:2 ratio. Cenobamate was rapidly absorbed, reaching its maximum plasma concentration (C_max) in 0.75 to 2.25 h, and was eliminated with a mean half‐life of 37.0 to 57.7 h. The C_max increased dose proportionally, whereas area under the concentration‐time curve increased more than dose proportionally, which was consistent with the findings in non‐Japanese subjects. The systemic exposure of cenobamate was comparable between Japanese and non‐Japanese subjects at all dose levels evaluated. All adverse events were mild in severity, and their incidence did not show dose‐dependent trends. Furthermore, there were no clinically significant issues in safety parameters, including sedation tests, neurologic examinations, and Columbia Suicide Severity Rating Scale interviews. In conclusion, the systemic exposure of cenobamate after a single dose in Japanese subjects increased by dose, which was similar to the pattern in non‐Japanese subjects. In addition, a single dose of cenobamate was well‐tolerated in the dose range of 50 to 400 mg in healthy Japanese subjects.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cenobamate is a novel antiseizure medication newly approved for the treatment of focal‐onset seizures in the United States and Europe. To date, properties of cenobamate including pharmacokinetics (PKs) have not been extensively studied in Asian people including Japanese people.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study evaluated the PKs and safety of a single oral dose of cenobamate in healthy Japanese subjects and compared the PKs with that in non‐Japanese subjects previously reported.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Cenobamate showed similar PK profiles in Japanese and non‐Japanese subjects, which suggests its negligible ethnic sensitivity. In addition, a single dose of cenobamate was well‐tolerated in healthy Japanese subjects. Our results indicate that the currently approved dosing regimen of cenobamate may also be applicable to Japanese patients with reasonable exposure and tolerability profiles.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Our study bridged the clinical pharmacology gap between ethnicities by providing new findings on the ethnic sensitivity as well as the PKs and safety of cenobamate in Asian people including Japanese people.     

Clinical outcomes following proton therapy for adult craniopharyngioma: a single-institution cohort study

Journal of Neuro-Oncology - Craniopharyngioma is a benign tumor that commonly develops within the suprasellar region. The tumor and treatment can have debilitating consequences for pediatric and...     

Identification and In Vivo Functional Characterization of Novel Compound Heterozygous BMP1 Variants in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal‐dominant inheritance, but many autosomal‐recessive genes have been reported. We applied whole‐exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.     

Physical stability of arginine-glycine-aspartic acid peptide coated on anodized implants after installation

PURPOSE

The aim of this study was to evaluate the stability of arginine-glycine-aspartic acid (RGD) peptide coatings on implants by measuring the amount of peptide remaining after installation.

MATERIALS AND METHODS

Fluorescent isothiocyanate (FITC)-fixed RGD peptide was coated onto anodized titanium implants (width 4 mm, length 10 mm) using a physical adsorption method (P) or a chemical grafting method (C). Solid Rigid Polyurethane Foam (SRPF) was classified as either hard bone (H) or soft bone (S) according to its density. Two pieces of artificial bone were fixed in a customized jig, and coated implants were installed at the center of the boundary between two pieces of artificial bone. The test groups were classified as: P-H, P-S, C-H, or C-S. After each installation, implants were removed from the SRPF, and the residual amounts and rates of RGD peptide in implants were measured by fluorescence spectrometry. The Kruskal-Wallis test was used for the statistical analysis (α=0.05).

RESULTS

Peptide-coating was identified by fluorescence microscopy and XPS. Total coating amount was higher for physical adsorption than chemical grafting. The residual rate of peptide was significantly larger in the P-S group than in the other three groups (P<.05).

CONCLUSION

The result of this study suggests that coating doses depend on coating method. Residual amounts of RGD peptide were greater for the physical adsorption method than the chemical grafting method.     

Prognostic Role of Carcinoembryonic Antigen Level after Preoperative Chemoradiotherapy in Patients with Rectal Cancer

Background

The prognostic role of post-chemoradiotherapy (CRT) carcinoembryonic antigen (CEA) level is not clear. We evaluated the prognostic significance of post-CRT CEA level in patients with rectal cancer after preoperative CRT.

Methods

We reviewed 659 consecutive patients who underwent preoperative CRT and total mesorectal excision for non-metastatic rectal cancer. Patients were categorized into two groups according to post-CRT serum CEA level: low CEA (<?5 ng/mL) and high CEA (≥?5 ng/mL).

Results

Median post-CRT CEA level was 1.7 ng/mL (range, 0.1–207.0). A high post-CRT level was significantly associated with ypStage, ypT category, tumor regression grade, and pre-CRT CEA level. The 5-year overall survival rate of the 659 patients was 87.8% with a median follow-up period of 57.0 months (range, 1.4–176.4). When the post-CRT CEA groups were divided into groups according to pre-CRT CEA level, the 5-year overall survival rates were significantly different (P?<?0.001 and P?=?0.001, respectively). Post-CRT CEA level was an independent prognostic factor for overall survival. Multivariate analysis revealed that operation method, differentiation, perineural invasion, postoperative chemotherapy, tumor regression grade, and post-CRT CEA level were independent prognostic factors for overall survival.

Conclusion

The level of serum CEA after preoperative CRT was an independent prognostic factor for overall survival in patients with rectal cancer.

     

Clinical Outcomes after Spinal Cord Stimulation According to Pain Characteristics

ObjectiveSpinal cord stimulation (SCS) is an effective treatment for chronic neuropathic pain. However, its clinical efficacy in regard to specific types of pain has not been well studied. The primary objective of this study was to retrospectively analyze the clinical outcomes of paddle-type SCS according to the type of neuropathic pain. MethodsSeventeen patients who underwent paddle-lead SCS at our hospital were examined. Clinical outcomes were evaluated pre- and postoperatively (3 months, 1 year, and last follow-up) using the Neuropathic Pain Symptom Inventory (NPSI). The NPSI categorizes pain as superficial, deep, paroxysmal, evoked, or dysesthesia and assess the duration of the pain (pain time score). Changes in NPSI scores were compared with change in Visual analogue scale (VAS) scores. ResultsAfter SCS, the pain time score improved by 45% (independent t-test, p=0.0002) and the deep pain score improved by 58% (independent t-test, p=0.001). Improvements in the pain time score significantly correlated with improvements in the VAS score (r=0.667, p=0.003, Spearman correlation). Additionally, the morphine milligram equivalent value was markedly lower after vs. before surgery (~49 mg, pared t-test, p=0.002). No preoperative value was associated with clinical outcome. ConclusionThe NPSI is a useful tool for evaluating the therapeutic effects of SCS. Chronic use of a paddle-type spinal cord stimulation improved the deep pain and the pain time scores.